Monitoring Patients with Iron Overload

Vinod Pullarkat, MD: The simple and practical way to measure iron overload in clinical practice is to measure serum ferritin. Serum ferritin is easy, it is cheap, and it’s readily available. The problem with serum ferritin is it’s an acute phase reactant. So, we know that there will be fluctuations in serum ferritin with inflammation, infection, which MDS patients often have. But, despite all these caveats, there is a relatively good correlation of serum ferritin with transfusion dependency and with liver iron concentration. Many studies have shown that. It’s actually not a bad marker, especially if it’s followed over time. Now, many centers have availability of MRI, and MRI measurements of liver iron concentration is pretty commonly done. There are still issues with the software used and how the values are calculated. The machines have to be calibrated appropriately to make sure that the LIC (liver iron concentration) measurements are accurate. In certain specialized centers, we have access to other measurements like cardiac iron and iron in endocrine glands, but those are not widely available. I think serum ferritin still remains the readily available, commonly done measure. And, MRI is increasingly becoming available.

For monitoring a patient on iron chelation, serum ferritin should be measured monthly to monitor these patients. Again, single values are less important than the trend over time. In patients where they have cardiac iron, there may be a discordance between iron chelation in the liver and iron chelation in the heart. Sometimes liver iron concentration can normalize and they can still have cardiac iron overload. So, that’s something to keep in mind.

Heather Leitch, MD, PhD: What’s most frequently used is a serum ferritin level. It’s, of course, not a perfect measure of iron overload, but trends in serum ferritin level can be informative. In my own practice, I also use transference saturation. It’s been shown in a couple of studies that a transference saturation over 80% or 85% predicts the presence of nontransfer and bound iron, which becomes labeled plasma iron, and is an indication of oxidative stress. Many of us think that the toxicity of iron overload may well be related to the ability of iron to transfer electrons and create oxygen-free radicals, which damage lipids, proteins, and nucleic acids and can have consequences for cells. This has been shown to be important in the hereditary anemias as well, and may underlie a lot of the toxicity that we see in acquired anemias.

In terms of monitoring treatment response, many of the same measurements are used, such as serum ferritin level, transference saturation. As I mentioned, that can be an indicator of oxidative stress. I’m always more comfortable when my patient’s transference saturation is less than 80% because I think that oxidative stress isn’t the major issue at that point. I also intermittently do measures of organ iron, such as T2* MRI, which can be done, for example, on a yearly basis.

As I mentioned, serum ferritin trends over time can be important. So, we don’t necessarily adjust doses based on one serum ferritin level, or even on a couple. It’s also possible that, early in chelation, the serum ferritin level can be elevated for quite a period of time before it actually starts to come down, and patients get quite worried if their serum ferritin is remaining elevated despite chelation. But, it’s important to reassure them that it will come down over time, provided that they’re not heavily transfusion-dependent and on a low dose of chelation, for example.

One of the things that’s been found to be important in the congenital anemias is that keeping a serum ferritin level less than 2500 portends superior cardiac disease-free survival. And so, again, with my MDS patients, I’m more comfortable if their ferritin is less than 2500. However, I don’t really think that we know what the important threshold is in MDS patients. MDS patients, of course, are older and may have other factors that are contributing to a risk of cardiac morbidity. So, it may well be that they’re still at risk, even at a lower ferritin level.

We also need to monitor for organ function. Liver function tests should be done routinely. We should also monitor for endocrine function. So, thyroid stimulating hormone, for example, calcium metabolism, bone metabolism. And we should measure for iron in the organs where this is available, such as through T2* MRI, or FerriScan, of the liver. This, of course, is not available widely in some areas of the world, and even in many areas of the country. But, it is useful where it is available. The final thing is to measure cardiac function on a regular basis by doing, for example, echocardiograms. If you can get cardiac MRI, that will measure the cardiac function, as well as iron deposition. But, where that’s not available, echocardiogram can be very useful.

Transcript Edited for Clarity

Transcript:

Vinod Pullarkat, MD: The simple and practical way to measure iron overload in clinical practice is to measure serum ferritin. Serum ferritin is easy, it is cheap, and it’s readily available. The problem with serum ferritin is it’s an acute phase reactant. So, we know that there will be fluctuations in serum ferritin with inflammation, infection, which MDS patients often have. But, despite all these caveats, there is a relatively good correlation of serum ferritin with transfusion dependency and with liver iron concentration. Many studies have shown that. It’s actually not a bad marker, especially if it’s followed over time. Now, many centers have availability of MRI, and MRI measurements of liver iron concentration is pretty commonly done. There are still issues with the software used and how the values are calculated. The machines have to be calibrated appropriately to make sure that the LIC (liver iron concentration) measurements are accurate. In certain specialized centers, we have access to other measurements like cardiac iron and iron in endocrine glands, but those are not widely available. I think serum ferritin still remains the readily available, commonly done measure. And, MRI is increasingly becoming available.

For monitoring a patient on iron chelation, serum ferritin should be measured monthly to monitor these patients. Again, single values are less important than the trend over time. In patients where they have cardiac iron, there may be a discordance between iron chelation in the liver and iron chelation in the heart. Sometimes liver iron concentration can normalize and they can still have cardiac iron overload. So, that’s something to keep in mind.

Heather Leitch, MD, PhD: What’s most frequently used is a serum ferritin level. It’s, of course, not a perfect measure of iron overload, but trends in serum ferritin level can be informative. In my own practice, I also use transference saturation. It’s been shown in a couple of studies that a transference saturation over 80% or 85% predicts the presence of nontransfer and bound iron, which becomes labeled plasma iron, and is an indication of oxidative stress. Many of us think that the toxicity of iron overload may well be related to the ability of iron to transfer electrons and create oxygen-free radicals, which damage lipids, proteins, and nucleic acids and can have consequences for cells. This has been shown to be important in the hereditary anemias as well, and may underlie a lot of the toxicity that we see in acquired anemias.

In terms of monitoring treatment response, many of the same measurements are used, such as serum ferritin level, transference saturation. As I mentioned, that can be an indicator of oxidative stress. I’m always more comfortable when my patient’s transference saturation is less than 80% because I think that oxidative stress isn’t the major issue at that point. I also intermittently do measures of organ iron, such as T2* MRI, which can be done, for example, on a yearly basis.

As I mentioned, serum ferritin trends over time can be important. So, we don’t necessarily adjust doses based on one serum ferritin level, or even on a couple. It’s also possible that, early in chelation, the serum ferritin level can be elevated for quite a period of time before it actually starts to come down, and patients get quite worried if their serum ferritin is remaining elevated despite chelation. But, it’s important to reassure them that it will come down over time, provided that they’re not heavily transfusion-dependent and on a low dose of chelation, for example.

One of the things that’s been found to be important in the congenital anemias is that keeping a serum ferritin level less than 2500 portends superior cardiac disease-free survival. And so, again, with my MDS patients, I’m more comfortable if their ferritin is less than 2500. However, I don’t really think that we know what the important threshold is in MDS patients. MDS patients, of course, are older and may have other factors that are contributing to a risk of cardiac morbidity. So, it may well be that they’re still at risk, even at a lower ferritin level.

We also need to monitor for organ function. Liver function tests should be done routinely. We should also monitor for endocrine function. So, thyroid stimulating hormone, for example, calcium metabolism, bone metabolism. And we should measure for iron in the organs where this is available, such as through T2* MRI, or FerriScan, of the liver. This, of course, is not available widely in some areas of the world, and even in many areas of the country. But, it is useful where it is available. The final thing is to measure cardiac function on a regular basis by doing, for example, echocardiograms. If you can get cardiac MRI, that will measure the cardiac function, as well as iron deposition. But, where that’s not available, echocardiogram can be very useful.